Cholinergic mechanisms and the role played by these mechanisms in the maintenance and regulation of spontaneous myocardial rhythm will be further investigated in the mammalian (rat and rabbit) heart. One objective of the work is to further substantiate the relative role of atrial and ventricular muscarinic receptors in the maintenance of normal cardiac rhythm, and to elucidate their possible involvement in arrhythmogenesis as well as in the therapeutic actions of certain anti-arrhythmic drugs. Data will be obtained from perfusion studies using intact mammalian hearts and from biochemical studies into neurohormonal-drug interactions, as well as agonist-antagonist interactions, at the level of the muscarinic receptor in subcellular preparations of myocardium. Another objective is to gain a deeper understanding of cholinergic biochemistry in the myocardium. Attempts will be made to obtain choline acetyltransferase, from both brain and heart tissue, in a sufficiently pure state to permit studies on control of enzymatic activity and on the relationship of the enzyme with the high affinity choline transport mechanism in membranes. Future studies will include drug-induced changes in membrane transport processes and also in the biogenesis, turnover, storage and release of muscarinic agonists in the myocardium. Observations from these varied studies will be correlated to further test the hypothesis that endogenous muscarinic agonists, possibly of extraneuronal origin, may play an important role in the initiation, regulation of alteration of spontaneous cardiac rhythm. Such a role would be clinically important since any pathologic or drug-induced alterations of these cholinergic mechanisms could be involved in the generation and/or correction of certain cardiac arrhythmias.